Beta emitter systems and results from clinical trials. state of the art

Vascular brachytherapy has been established as the standard of care for the treatment of in-stent restenosis (ISR). Both beta and gamma emitters are currently in use for the prevention of ISR recurrence. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view, and a wide variety of beta sources are available for this application. This review is intended to summarize the clinical trials utilizing beta emitter systems for the treatment of ISR and de novo lesions and their subsequent results.     

Progress in clinical trials for coronary arterial restenosis using beta radiation sources

Vascular brachytherapy has yet taken the leap into progression from emerging technology to standard of care dependent on the outcome of clinical trials. Data collected from early pilot trials and on-going clinical trials indicate that such a progression is achievable. Three-year follow-up data from patients treated with intracoronary radiation for the prevention of restenosis are now available. Data from larger trials are being assessed using angiographic and intravascular ultrasound analysis. The beta radiation studies are demonstrating different levels of efficacy, raising new issues regarding dosimetry and potential complications. Past trials have examined the use of vascular brachytherapy for recurrence prevention of restenosis in patients with in-stent restenosis. New data related to the use of liquid-filled balloon systems and radioactive stent are also being collected. This article updates the current status of clinical trials in vascular brachytherapy utilizing beta emitters, highlighting preliminary results and assessing their implications for the development of this field.     

Brachytherapy with gamma radiation of a coronary artery for in-stent restenosis may induce the regression of in-stent restenosis of an adjacent coronary artery without angioplasty. First case report and review of the literature

Here, we present a case of a 63-year-old male who presented with in-stent restenosis of two coronary arteries simultaneously (mid circumflex and proximal ramus). After the brachytherapy of the circumflex artery for in-stent restenosis, the patient refused the staged procedure for the ramus in-stent restenosis. After approximately 2 years, the patient underwent coronary angiography for recurrent chest pain. Surprisingly, the proximal ramus stent showed marked regression of in-stent restenosis. We hypothesized that the gamma brachytherapy of the circumflex artery could have induced the regression of in-stent restenosis of the adjacent ramus artery due to the deep tissue penetration of gamma radiation. Based on our observation, we believe that in the treatment of in-stent restenosis of a coronary artery, the initial balloon angioplasty may not be as important as the radiation itself. This observation warrants further study to evaluate the effect of external or internal radiation on in-stent restenosis without balloon angioplasty. If our hypothesis is confirmed, the treatment of in-stent restenosis with external radiation could substantially simplify the treatment of this disease. This case report follows a brief review of the literature.     

Chronic total occlusion due to diffuse in-stent restenosis: is brachytherapy the solution?

Percutaneous coronary intervention of chronic total occlusions (CTO) is associated with a significantly higher incidence of reocclusion and restenosis compared with non-total occlusions. Randomized and observational trials have demonstrated the effectiveness of intracoronary brachytherapy (ICBT) for the prevention of recurrent in-stent restenosis. However, limited data are available on the effectiveness of ICBT in patients with totally occluded in-stent restenosis. The authors assessed the long-term outcome of patients treated with intracoronary gamma radiation for totally occluded in-stent restenotic lesions. Percutaneous coronary intervention and subsequent catheter-based irradiation with iridium-192 was performed in 100 patients (103 vessels) with diffuse in-stent restenosis. At baseline, CTO of the target vessel at the site of the stent was present in 15 vessels (14.5%). Follow-up data were collected during follow-up visits and from telephone interviews. Repeat coronary angiography was performed in symptomatic patients with clinical restenosis. Clinical and angiographic characteristics were similar between the two groups, although there was a trend towards more unstable angina at the index procedure in CTO patients (66.7% versus 41.4%; p = 0.12) compared with patients without non-total occlusions. A higher percentage of patients (53.3%) with CTO required longer radiation sources (14 seeds, covering a length of 55 mm), compared with 23.9% of patients with non-total occlusion (p = 0.04). With a mean follow-up period of 47.5 +/- 24.0 months, major adverse cardiac events (MACE) were observed in 10 of 15 patients (66.7%) with CTO compared with 25 out of 88 patients (28.4%) without CTO (p = 0.009). According to multivariate analysis, total occlusion of the target vessel at baseline was the single independent predictor of MACE at one-year follow-up (relative risk 16.2, 95% confidence interval 4.2-62.9; p < 0.0001). This study shows that the use of gamma radiation for the prevention of recurrence of in-stent restenosis in patients with CTO does not seem to be as effective as in patients with non-total occlusions. Furthermore, CTO was an independent predictor of worse outcome at long-term follow-up in this study.     

Prevention of in-stent restenosis: towards an in situ treatment?

The use of intracoronary stents represent a major breakthrough in the armamentarium of interventional cardiology. Stents reduce significantly the incidence of recurrent stenosis (in-stent restenosis) via an improved post-procedure luminal diameter and an abrogation of the constrictive remodeling of the arterial wall. However, stent-related arterial injury results in intense proliferative and inflammatory responses and severe intimal hyperplasia, which, in 20% to 40% of the patients, may end up with clinically significant in-stent restenosis. Efficient prevention of in-stent restenosis has yet to be found. Systemic treatments have failed because they don't take into account the specific physiopathology and, most importantly, the focal nature of in-stent intimal hyperplasia. Hence, local prevention appears to be a straightforward approach to the unsolved issue of in-stent restenosis. In situ beta- or gamma-irradiation (brachytherapy) has received much attention as a curative treatment of in-stent restenosis but is not indicated for prevention. In contrast, drug-releasing stents have been tested in experimental models and have already provided very promising results in randomized clinical trials. Most of clinical studies have been performed with the antiproliferative agents sirolimus and paclitaxel, but other agents are under scrutiny. In addition, important research is carried out, in which the efficacy of antiproliferative genes is investigated. Clearly, drug-releasing stents are on the verge of profoundly modifying our practice of interventional cardiology. However, several questions remain unanswered as regard to the long term efficacy/toxicity and the cost-effectiveness of this new approach.     

Novoste Beta-Cath integrity test with the active source train

Intravascular brachytherapy (IVB) to prevent restenosis is currently being performed using several different commercial delivery devices. The Novoste Beta-Cath system uses a source train of 90Sr/90Y pure beta emitters and two gold radiopaque markers. A nonactive transfer device with dummy sources is also supplied to test the delivery catheter. We have developed an alternate procedure using an acrylic shield to test both the active transfer device and delivery catheter prior to patient treatment.     

Endovascular brachytherapy in coronary arteries: the Rotterdam experience

Purpose: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far.Methods and Materials: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n=31), for compassionate use (n=25), in the Beta-Cath System trial (n=27) and in the Beta Radiation in Europe (BRIE, n=14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 μCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 μCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively.Results: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges.Conclusions: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.     

Intracoronary radiation with gamma wire inhibits recurrent in-stent restenosis

To study the safety and efficacy of intracoronary gamma radiation delivered via a new high-activity (192)Ir source wire for the treatment of in-stent restenosis. In-stent restenosis results from neointimal tissue proliferation especially in its diffused form and presents a therapeutic challenge. Gamma radiation has been shown to decrease neointima formation within stents in animal models and in initial clinical trials. A total of 26 patients with in-stent restenosis underwent successful intervention and was treated with open-label (192)Ir using a high-activity line source. The specific activity of the source wire was 372+/-51 mCi, and the dwell time was 10.8+/-1.9 min. Primary endpoints were freedom from death, myocardial infraction (MI), and repeat target lesion revascularization (TLR) at 6 months. Secondary endpoints included angiographic restenosis and intravascular ultrasound (IVUS) neointimal hyperplasia. Procedural success was high (96.2%), and in-hospital and 30-day complications were low with no deaths, MI, or requirement for repeat revascularization. At 6 months, event-free survival was 85%: one patient required repeat PTCA, one underwent bypass surgery, and two had an MI. Baseline lesion length measured 15.77 mm. Follow-up angiography was available in 21/25 (84%) patients. The binary restenosis rates were 19.0% (4/21) in-stent and 23.8% (5/21) in-lesion. Follow-up IVUS was available in 20/25 patients. There was no increase in intimal hyperplasia from postintervention to follow-up (3.11.8 vs. 3.41.8 mm(2); P=.32). Eight patients had a reduction of neointimal intimal tissue at follow-up. These results indicate that intracoronary gamma radiation with the Angiorad source wire is safe and effective in preventing in-stent restenosis.     

Review of endovascular brachytherapy physics for prevention of restenosis

Intraluminal irradiation of coronary and peripheral arteries has been shown to reduce neointimal hyperplasia following balloon angioplasty, thereby inhibiting restenosis. Several irradiation techniques are being investigated, including temporary intravascular insertion of high activity gamma- or beta-emitting seeds and wires; inflation of dilatation balloon catheter with radioactive liquid or gas; insertion of miniature x-ray tubes via coronary catheters; permanent implantation of radioactive stents; and postangioplasty fractionated external beam irradiation. Unlike conventional brachytherapy, intravascular treatment of restenosis requires accurate knowledge of dose at distances of 0.5-5 mm from the radioactive source. This requirement presents special problems with regard to source calibration and dose specification, because dose gradients at such close distances from a radioactive source are extremely large. This makes it virtually impossible to define the characteristics of an ideal radiation source without some knowledge of the location and radiosensitivity of the target tissues, plus the radiotolerance of normal tissues. Hence, the current debate over whether beta or gamma sources are to be preferred. Imprecise knowledge of dose-volume effects for coronary arteries, plus uncertainties in the biological time sequencing of restenosis fuel a second debate on whether external beam treatments may be efficacious, and whether or not permanent radioactive stents may prove superior to high dose, single fraction brachytherapy. We review here the dosimetric properties of the various irradiation techniques and isotopes that have been proposed, including aspects of radiation safety, dose homogeneity, and practical aspects of source delivery.     

Methods to improve dose uniformity for radioactive stents in endovascular brachytherapy

Intravascular brachytherapy (IVBT) has rapidly gained acceptance as a new treatment modality for reducing restenosis and improving the success rate of percutaneous transluminal coronary angioplasty (PTCA). Recent clinical results on patients treated with beta-emitting 32P stents suggest that radiation reduces in-stent restenosis but may exacerbate neointimal growth at the edges of the stents. This has been referred to as the "candy wrapper effect." It is well known that radioactive stents yield extremely inhomogeneous dose distributions, with low doses delivered to tissues in between stent struts, at the ends of the stent, and also at depth. Some animal model studies suggest that low doses of radiation may stimulate rather than inhibit neointimal growth in an injured vessel, and it is hypothesized that dose inhomogeneity at the ends of a stent may contribute to the candy wrapper effect. We present here a theoretical study comparing dose distributions for beta stents vs. gamma stents; "dumbbell" radioactive loaded stents vs. uniformly loaded stents; and stents with alternate strut design. Calculations demonstrate that dose inhomogenieties between stent struts, at the ends of stents, and at depth can be reduced by better stent design and isotope selection. Prior to the introduction of radioactive stents, criteria for stent design included factors such as trackability, flexibility, strength, etc. We show here that if stent design also includes criteria for strut shape and spacing that improved dose distributions are possible, which in turn could reduce the candy wrapper effect.     

Dosimetric penumbra effects in catheter-based intravascular brachytherapy using a centered photon or beta line source

Purpose: In catheter-based intravascular brachytherapy, either photon or beta emitters are often used in a linear arrangement so that blood vessels of 10-30 mm lengths can be treated. With a line source, the dose gradient in the radial direction and longitudinal direction depend on the type of radionuclides used in the treatment. The purpose of this study was to investigate the dose fall-off at the edges of a linear source in a blood vessel for different types of photon and beta emitters.Materials/Methods: Dose distributions were calculated on cylindrical blood vessels of various radii. Radioactive sources of 192Ir, 125I, 103Pd, 188Re, 32P, and 90Y/Sr were studied. All the sources were assumed to be in the form of a line. The dose rate at a point in space produced by a radioactive source was computed by integrating the point dose rate kernel of the corresponding radionuclide over the radioactive line. The point dose rate kernel was computed with Monte Carlo simulation of radiation transport. The edge effects were characterized with three newly defined quantities: longitudinal dose uniformity (LDU), effective coverage length (ECL), and margin length (ML). LDU was defined as the ratio of dose at a distance along the long axis of the vessel to the dose at center. ECL was defined as the length over which the LDU was greater than 0.95. ML was defined as half of the length difference between source length L and ECL, which is essentially the length segment at each edge that is covered by the source physical length but is being underdosed.Results: All beta emitters provided more uniform dose distributions and covered a larger portion of blood vessels longitudinally than photon emitters. Typical MLs were 2-3 mm for beta emitters and 4-6 mm for gamma emitters. As the radial depth of the point of interest increased, both the LDU and ECL decreased and ML increased. The ML increased from 2 to 3 mm for beta emitters and from 4 to 6 mm for photon emitters when the radial depth of the point of interest increased from 1.5 to 2.5 mm (typical proximal and distal media points for a 3-mm diameter lumen). The ML increased with increasing source length for all radionuclides. For beta emitters the ML increased initially from 1.5 mm to more than 2.5 mm as source length increased from 5 to 10 mm. When the source length was longer than 15 mm, the ML remains nearly constant, about 3 mm. For photon emitters, ML increased continuously from 1.5 mm to more than 6.0 mm, as source length increased from 5 to 50 mm.Conclusions: A formalism to quantify the dose uniformity along the length of a blood vessel undergoing catheter-based intravascular brachytherapy has been developed. This formalism was used to study the edge effects at the ends of several beta and photon sources. The results indicated that for a centered source the ML at each end due to penumbra effects was about 2 to 3 mm for beta emitters; about 4-6 mm for photon emitters. The ML increases as the radial depth of point of interest in the vessel increases. The ML increases also with increasing source length, especially for photon sources.     

Pathology of in-stent restenosis

The process of in-stent restenosis parallels wound healing responses. Stent deployment results in early thrombus deposition and acute inflammation, granulation tissue development, and ultimately smooth muscle cell proliferation and extracellular matrix synthesis. The severity of arterial injury during stent placement correlates with increased inflammation and late neointimal growth. These pathological findings provide useful targets for therapies aimed at reducing the incidence of in-stent restenosis.     

A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes

Since their first introduction, stents have revolutionised the treatment of atherosclerosis; however, the development of in-stent restenosis still remains the Achilles' heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models, whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent-induced mechanical injury, specifically changes within the extracellular matrix, have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study, a mechanistic multi-scale mechanobiological model of in-stent restenosis using finite element models and agent-based modelling is presented, which allows quantitative evaluation of the collagen matrix turnover following stent-induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimisation of the mechanical parameters involved in stent design.     

Intracoronary brachytherapy following drug-eluting stent failure. It's still not time to hang up the spikes!

Drug-eluting stents (DES) have significantly reduced the incidence of restenosis. Although the results obtained with these novel antiproliferative devices are encouraging, recent reports have shown that DES are not completely immune from restenosis. Therefore, the broad use of DES has inevitably led to a major issue: treatment of DES failure. Intracoronary brachytherapy (IBT) represents an important advancement for treatment of in-stent restenosis (ISR) and has led to important pathophysiological insight on the restenotic process. To date, IBT, when properly used, still represents the gold standard for treatment of ISR. However, experience with IBT is for treatment of ISR occurring with bare metal stents (BMS). Whether IBT may be used with the same safety and efficacy profile as an adjunctive treatment for ISR following DES implantation is still unknown. In this article, we report the outcome of a series of patients with DES failure treated with IBT. IBT for treatment of DES failure was shown to be both safe and efficient and, therefore, until ISR exists, IBT still remains an important player in this growing and even more challenging setting.     

Mechanistic evaluation of long-term in-stent restenosis based on models of tissue damage and growth

Development and application of advanced mechanical models of soft tissues and their growth represent one of the main directions in modern mechanics of solids. Such models are increasingly used to deal with complex biomedical problems. Prediction of in-stent restenosis for patients treated with coronary stents remains a highly challenging task. Using a finite element method, this paper presents a mechanistic approach to evaluate the development of in-stent restenosis in an artery following stent implantation. Hyperelastic models with damage, verified with experimental results, are used to describe the level of tissue damage in arterial layers and plaque caused by such intervention. A tissue-growth model, associated with vessel damage, is adopted to describe the growth behaviour of a media layer after stent implantation. Narrowing of lumen diameter with time is used to quantify the development of in-stent restenosis in the vessel after stenting. It is demonstrated that stent designs and materials strongly affect the stenting-induced damage in the media layer and the subsequent development of in-stent restenosis. The larger the artery expansion achieved during balloon inflation, the higher the damage introduced to the media layer, leading to an increased level of in-stent restenosis. In addition, the development of in-stent restenosis is directly correlated with the artery expansion during the stent deployment. The correlation is further used to predict the effect of a complex clinical procedure, such as stent overlapping, on the level of in-stent restenosis developed after percutaneous coronary intervention.

     

Why and how to avoid stenting during brachytherapy

Intracoronary radiation is a promising therapy to reduce restenosis after percutaneous coronary intervention. It may be anticipated that radiation and intracoronary stents - the current standard coronary revascularization procedure - have a synergic antirestenosis effect. However, this potential benefit has not been proven in the clinical scenario. Indeed, this combined approach (stenting plus brachytherapy) may even be harmful. Delayed endothelialization and late stent malapposition are important drawbacks of implanting a metallic prosthesis in the setting of radiation therapy. Owing to the relatively high frequency of late thrombosis after stenting irradiated coronary arteries, the Food and Drug Administration required that the labeling of both gamma- and beta-radiation devices recently approved for clinical use explicitly advise avoidance of the placement of new stents. The pathophysiologic aspects as well as the clinical implications of the implantation of a new stent in association with radiation delivered by radioactive stents or catheter-based systems are discussed in this paper.     

Excimer laser coronary angioplasty and intracoronary radiation for in-stent restenosis: Six-month angiographic and clinical outcomes

Background: The purpose of this study was to evaluate 6-month clinical and angiographic outcomes in patients treated with excimer laser coronary angioplasty (ELCA) and intracoronary radiation (ICR) for in-stent restenosis (ISR).Methods: A consecutive series of 175 patients with ISR treated with ELCA+ICR (gamma and beta emitters) were compared to 33 patients with ISR treated with ELCA alone. Baseline characteristics were similar between groups. ELCA+ICR and ELCA-alone patients had similar lesion lengths (25.0±12.0 vs. 24.0±16.8 mm, P=NS) in predominantly saphenous vein grafts (SVG, 38% vs. 42%, P=NS).Results: Procedural success was high (ELCA+ICR, 97.0% vs. ELCA alone, 98.5%, P=NS), with no perforations or acute vessel closures. ELCA+ICR therapy reduced target vessel revascularization (TVR; 27% vs. 64%, P<.0001) and major adverse cardiac events [MACE: death, myocardial infarction (MI), or TVR; 30% vs. 64%, P<.0001] compared to ELCA alone. Late loss was 0.66±0.90 mm in ELCA+ICR patients and 0.85±0.60 mm in ELCA-alone patients (P=NS). Angiographic binary restenosis (>50%) was significantly reduced with adjunctive ICR (28% vs. 54%, P=.014).Conclusion: Radiation therapy with ELCA significantly reduces angiographic binary restenosis at 6 months in patients with diffuse ISR, driven predominantly by reduced percutaneous TVR.     

内皮祖细胞在支架术后再内皮化中应用的研究进展

经皮冠状动脉介入治疗的应用改善了冠心病患者的临床症状及预后,但现在困扰人们的问题是作为其术后并发症之一的支架内再狭窄发病率仍然很高。大量的研究证实,内膜增生在支架内再狭窄的形成中起主导作用,所以提高受损内膜再内皮化的速度是防止支架内再狭窄的一个重要措施。新近的研究表明,内皮祖细胞能参与损伤后血管内皮修复,促进受损血管内膜的再内皮化,因此,在防止支架内再狭窄中将得到进一步的研究与应用。因此,本文就内皮祖细胞在支架术后再内皮化中应用的研究进展做一综述。     

The role of intravascular ultrasound imaging in vascular brachytherapy

Intracoronary brachytherapy has recently emerged as a new therapy to prevent restenosis. Initial experimental work was achieved in animal models and the results were assessed by histomorphometry. Initial clinical trials used angiography to guide dosimetry and to assess efficacy. Intravascular ultrasound (IVUS) permits tomographic examination of the vessel wall, elucidating the true morphology of the lumen and transmural components, which cannot be investigated on the lumenogram obtained by angiography. This paper reviews the use of IVUS in the clinical studies of brachytherapy conducted to date. IVUS allows clinicians to make a thorough assessment of the remodeling of the vessel and appears to have a major role to play in facilitating understanding of the underlying mechanisms of action in this emerging field. The authors propose that state-of-the-art IVUS techniques should be employed to further knowledge of the mechanisms of action of brachytherapy in atherosclerotic human coronary arteries.